SUBSTANTIVE ANTIMICROBIAL PHOSPHATES

Abstract: Noningestible, sustained release compositions comprising antimicrobial phosphate esters, and methods of using them, are described.

Description: SUBSTANTIVE ANTIMICROBIAL PHOSPHATES BACKGROUND OF THE INVENTION Consumer products sometimes include antimicrobials to reduce or inhibit growth or adhesion of microorganisms present on surfaces such as skin, clothing or mucosal producing body cavities. For example, triclosan is a broad spectrum antimicrobial agent which is compatible with dentifrice components, Marsh, P. D., Dentifrices Containing New Agents for the Control of Plaque and Gingivitis: Antimicrobial Aspects. J. Clin. Periodontol. 18:462-67 (1991). Ordinarily, though, antimicrobials are capable of reducing or eliminating microorganisms for a period of time which is a function of their surface retention properties. Additionally, the inclusion of antimicrobials can lead to off-odors or tastes, commonly referred to as "mediciney" or "chemical" tastes or smells. A relatively tasteless and/or odorless composition containing a substantive compound with sustained antimicrobial effects or properties is therefore desirable. SUMMARY OF THE INVENTION The present invention relates to a noningestible sustained release antimicrobial composition, comprising, by weight of the composition, from about 0 001% to about 25% of one or more compounds of the formula; where R is an antimicrobial agent; R' and R" are independently selected from the group consisting of R, adherent components, physiologically relevant metal cations, organic cations, and hydrogen; X, X, and X" are independently selected from the group consisting of oxygen, nitrogen, and sulfur, and n is an integer greater than or equal to 1. DETAILED DESCRIPTION OF THE INVENTION The subject invention relates to a composition comprising a noningestible sustained-release antimicrobial composition, comprising, by weight of the composition, from about 0.001% to about 25% of one or more compounds of the formula; where R is an antimicrobial agent; R' and R" are independently selected from the group consisting of R, adherent components, physiologically relevant metal cations, organic cations, and hydrogen; X, X, and X" are independently selected from the group consisting of oxygen, nitrogen, and sulfur, and n is an integer greater than or equal to 1. R' may equal R", preferably wherein R' and R" are independently selected from the group consisting of calcium, zinc, manganese, copper, tin and magnesium. By "noningestible" is meant that the present composition is not intended for systemic usage. For example, it is not meant to be swallowed, except for the minimal ingestion which may occur during use of a mouthrinse, toothpaste or nasal spray. Preferred "physiologically relevant metal cations" are selected from the group consisting of sodium, potassium, calcium, zinc, copper, manganese, tin and magnesium. Most preferred are sodium and potassium. "Organic" cation as used herein refers to cations that contain positively charged nitrogen, phosphorous, oxygen, or sulfur atoms. Such cations may contain more than one positively-charged site and, in the case of oligomers or polymers containing nitrogen, phosphorous, oxygen, or sulfur atoms, many positively-charged centers may exit. Preferred organic cations include ammonium (most preferred), protonated amines such as protonated glucosamine, and partially or fully protonated amine-containing polymers such as protonated chitosan. Phosphate Derivatives: The present invention compositions contain one or more antimicrobial phosphate derivatives. These compounds may be synthesized by phosphorylating a least one antimicrobial component. The compounds herein include compounds formed by linking at least one antimicrobial component to an adherent component via a phosphate bridge. Antimicrobial components may also be linked to phosphorous via two functional groups or attachment sites. Furthermore, the phosphate derivatives described above may be bound via Coulombic interaction with charged compounds or materials, including polymers. The present compositions may deliver the desired antimicrobial effect through the action of the phosphate derivative itself, or through the release of the antimicrobial component from the compound after its cleavage by phosphatase enzymes. Phosphatase enzymes are commonly present in the oral cavity and other mucosal producing body cavities, and on skin and clothing (which has been in contact with skin). By phosphatase enzyme is meant acid, neutral, or alkaline phosphatases and pyrophosphatases. The term "adherent component" as used herein refers to either monomers, oligomers, or polymers having hydroxy, amino, or thiol functionalities which are capable of forming either ester amido, or thioester linkages with phosphorυs(V) atoms. The monomers, oligomers, or polymers may also possess additional hydroxy, amino, or thiol groups which may either remain unsubstituted or be linked via ester amido, or thioester linkages to a phosphorus(V) atom which is also attached to an antimicrobial agent. Preferred compounds are selected from the group consisting of C12-C18 diacyl glycerol, partially hydrolyzed vinyl acetate/ethylene copolymer, cellulose, carboxymethylcellulose, chitin, glucose, glucosamine, silica gel, glycerol, and methyl vinyl ether-maletc acid. In preferred antimicrobial phosphate formulas herein: R is preferably an antimicrobial component selected from the group consisting of 2,4,4'-trichloro-diphenyl ether-2'-yl, 2-phenoxyethanyl, chlorhexidine, thymyl; R' and R" are preferably R, C12-C18 diacyl glycerol, partially hydrolyzed vinyl acetate-ethylene copolymer, cellulose, carboxymethyl cellulose, chitin, glucosamine, silica gel, glycerol, lower alkyl vinyl ether maleic acids, sodium, potassium, calcium, zinc, magnesium, ammonium, protonated amines, partially or fully protonated amine-containing polymers, and hydrogen; X, X, and X" are independently selected from the group consisting of oxygen, nitrogen, and sulfur, and n is preferably an integer from 1 to 3, most preferably 1 or 2. Preferred antimicrobial phosphates herein are thymyl monophosphate, 2,4,4'- trichloro-2'-hydroxy-diphenyl ether monophosphate (also referred to as triclosan monophosphate), 2-phenoxyethanyl monophosphate, and poly ([l,4]-B-D-glucosyl- 6-(2-phenoxyethenyl phosphate). More preferred are thymyl monophosphate, and poly ([l,4]-B-D-glucosyl-6-(2-phenoxyethenyl phosphate). 2,4,4'-trichloro-diphenyI ether (triclosan) monophosphate is preferable for use in topical skin preparations, deodorants, nasal sprays, and laundry products herein, but not for dental preparations herein, such as toothpaste and mouthrinse. When the composition is in the preferred form of a liquid or granular laundry detergent, poly ([l,4]-B-D-glucosyl-6-(2-phenoxyethenyl phosphate) is the preferred compound. When the composition is in the form of an oral mouth rinse, thymyl monophosphate is the preferred compound. When the composition is in the form of a toothpaste, thymyl monophosphate is the preferred compound. When the composition is in the form of a topical skin preparation, the preferred compound is 2 J 4,4 , -trichloro-2'- hydroxy-diphenyl ether monophosphate. When the composition is in the form of a nasal spray, the preferred compound is 2,4,4'-trichloro-2'-hydroxy-diphenyl ether monophosphate or thymyl monophosphate. The antimicrobial phosphates are used in the present invention at levels of from about 0.001% to about 25%, preferably from about 0.01% to about 15%, most preferably from about 0.1% to about 5%, by weight of the composition. Health Care Compositions The present compositions are preferably health care compositions, preferably containing a safe and effective amount of one or more actives. The term "active" as used herein means an agent which provides an effect greater than an excipient such as agents providing nutritional, therapeutic, medicinal, antimicrobial, and/or aesthetic benefit, and those commonly used in health care products. The phrase "suitable for oral or topical administration" as used herein means any formulation that is suitable for the convenient administration of the composition whereby the composition is intentionally, retained in the oral cavity for any period of time, placed in contact with internal mucous membranes of the body, such as those of the nose, mouth, or throat whether by direct or indirect application or inhalation to the nasal passages, or applied to the surfaces of the skin for therapeutic reasons or reasons other than for cosmetic benefit. Oral compositions herein are preferably not, in the ordinary course of usage, intentionally swallowed for purposes of systemic administration of particular therapeutic agents, but are rather retained in the oral cavity for a time sufficient to contact substantially all or most of the dental surfaces and/or oral tissues. The phrase "a safe and effective amount", as used herein, means a sufficient amount of material to provide the desired benefit without undue adverse side effects (such as toxicity, irritation or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific safe and effective amount will vary with such factors as the particular condition that is being treated, the severity of the condition, the duration of the treatment, the physical condition of the patient, the nature of concurrent therapy (if any), and the specific formulation and optional components employed. Carrier Materials: In formulating the compositions of this invention the phosphate derivative will preferably be incorporated into a carrier which may be completely inert or which may be or contain other active ingredients. The term "carrier materials", as used herein, means one or more compatible substances suitable for administration to a human or lower animal. The term "compatible", as used herein means that the components of the compositions are capable of being commingled with phosphate derivatives, actives, and with each other, in a manner such that there is no interaction which would substantially reduce the efficacy of the present compositions under ordinary use situations. Carrier materials must also be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated. A wide variety of carriers will be suitable depending upon the end use of the compositions. The phosphate derivatives can be incorporated into a range of topical compositions. Topical compositions include compositions applied to, or which in normal usage come in contact with, the internal membranes of the body such as those of the nose, mouth, or throat, whether by direct or indirect application. Such compositions include (but are not limited to) nasal sprays, dentifrices, oral rinses, lozenges, foams, gels, and throat sprays. Topical compositions may also be compositions applied to the external surfaces of the body for therapeutic reasons or reasons other than for cosmetic benefit. Such compositions include ointments, lotions, gels, and creams. Preferred compositions of the present invention are health care compositions such as dentifrices, oral rinses, and nasal sprays. The present compositions preferably comprise from about 0.1% to about 99%, and preferably from about 1% to about 99%, by weight of the composition. Suitable carrier materials herein, depending on intended end use, are selected from the group consisting of solvents, suspending agents, solubilizing agents, diluents, surfactants, buffers, lubricants, thickeners, emulsifiers, flavoring agents, colorants, humectants, sweeteners, co-solvents, binders, disintegrating agents, flow-inducing agents, coolants, wetting agents, antioxidants, stabilizers, and tableting agents. Preferably, the compositions herein include from about 85% to about 99.99%, more preferably from about 90% to about 99.05%, most preferably from about 95% to about 99.5%, by weight of the composition, of carrier material. Dentifrices Dentifrice compositions may be of the liquid, paste, powder or gel type. These compositions will usually comprise a finely divided abrasive or polishing material, e.g. precipitated chalk, silica, magnesium silicate, calcium polymetaphosphate, aluminum hydroxide or other similar materials well known in the art. Abrasive materials are more fully described in U.S. Patent 3,070,510, Cooley et al., December 25, 1962, which is incorporated herein by reference. Toothpaste compositions additionally contain a surfactant or foaming agent. Suitable surfactants are those which are reasonably stable and foam throughout a wide pH range, including non-soap anionic, nonionic, cationic, zwitterionic and amphoteric organic synthetic detergents. These surfactants are disclosed by Gieske et al. in U.S. Patent 4,051,234, issued September 27, 1977, also incorporated herein by reference. Optional ingredients in dentifrice compositions include flavoring agents, colorants, buffers, lubricants, thickeners, emulsifiers or plasticizers, and humectants. Dentifrice carrier materials typically comprise from about 50% to about 94%, and preferably from about 6O% to about 80%, by weight of the dentifrice compositions. Oral Rinses Oral rinses usually comprise an aqueous, alcoholic, or aqueous-alcoholic solution of an antiseptic which is often colored or flavored for palatability. Optional ingredients include humectants, surfactants, sweeteners, emulsifying agents, fluoride ion sources, tartar control, and anti-plaque agents. Oral rinse products may also be formed by dissolving a powder or tablet containing stannous gluconate in water just prior to use. Conventional oral rinse compositions generally comprise from about 0% to 60% ethyl alcohol, 0% to 20% of a humectant, 0% to 2% emulsifying agents, 0% to 0.5% sweetening agents, 0% to 0.3% flavoring agents and the balance water. Although water itself may make up the entire carrier, typical oral formulations also contain a co-solvent including but not limited to alcohol, propylene glycol, glycerin, sorbitol solution, and the like, to assist solubilization and incorporation of water-insoluble ingredients, flavoring oils and the like into the composition. In general, the compositions preferably contain from about 5 to about 25 volume/volume percent of the co-solvent, most preferably from about 10 to about 20 volume/volume percent of the co-solvent. Oral compositions herein are preferably toothpaste, mouthrinse (most preferred), or liquid dentifrice. Sodium fluoride is preferably included in dentifrice compositions herein. Components to be added should be safe for oral use. Nasal Spravs Carriers suitable for nasal administration provide a product which is delivered to the nasal passages. Such carriers may be for example, aqueous or aerosol and are more fully described in Remington's Pharmaceutical Sciences (17th Edition, 1985), which is incorporated herein by reference. Such product forms include (but are not limited to) nasal solutions for use as drops or as sprays, nasal suspensions, nasal ointments, nasal gels, or other vehicles suitable for nasal administration. Preferred nasal dosage forms are solutions, suspensions, and gels, which normally contain sodium chloride in a major amount of water (preferably purified water). Other ingredients including but not limited to: pH adjusters such as sodium hydroxide; emulsifiers or dispersing agents; buffering agents such as sodium bicarbonate; preservatives such as benzyl alcohol, parabens, benzalkonium chloride, chlorhexidine gluconate and disodium EDTA; agents for regulating isotonicity such as sodium chloride, boric acid, potassium phosphate and propylene glycol; wetting agents; thickening agents such as methylcellulose, zanthan gum, carboxymethyl cellulose, and carbomer, humectants such as sorbitol, propylene glycol, sorbitol, and glycerol; surfactants such as polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydrides; and mixtures thereof may also be present. Other Carriers The invention compositions may be formulated with a wide variety of carrier materials in addition to those already disclosed. Some examples of substances which can serve as carrier materials are sugars such as lactose, glucose, and sucrose; starches such as comstarch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; dicalcium phosphate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oO, and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar, alginic acid; as well as other non-toxic compatible substances used in consumer or health care formulations. Coolant materials may also be included as carrier materials in the invention compositions. Preferred coolants in the present compositions are the paramenthane carboxyamide agents such as N-ethyl-p-menthane-3-carboxamide (known commercially as "WS-3"), and 3-l-menthoxypropane-l,2-diol (known commercially as "TK-10"), and mixtures thereof. These coolants are described in PCT Patent Application Publication WO 92-17164, to Upson et al., published October 15, 1992. TK-10 is also described in U.S. Patent 4,459,425 to Amano et al., issued July 10, 1984; and WS-3 and the paramenthane carboxyamide agents are also described in U.S. Patent 4,136,163 to Watson et al., issued January 23, 1979. The disclosures of all three of these patent publications are incorporated by reference herein in their entirety. When desired or necessary, suitable binders, lubricants, and disintegrating agents can also be incorporated in the compositions. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia sodium alginate, carboxymethylcellulose, microcrystalline cellulose, polyethylene glycol and waxes. Lubricants may include, for example, starch, methylcellulose, agar, bentonite, guar gum, etc. Wetting agents such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, sweetening agents, excipients, stabilizers, antioxidants, and preservatives can also be present. Active: The invention compositions may also contain a safe and effective amount of one or more additional actives. Some additional actives that are useful in these compositions include (but are not limited to) antimicrobial agents such as iodine, sulfonamides, mercurials, bisbiguanides, or phenolics; antibiotics such as tetracycline, neomycin, kanamycin, metronidazole, or clindamycin; anti-inflammatory agents such as aspirin, acetaminophen, naproxen, ibuprofen, flurbiprofen, indomethacin, eugenol, or hydrocortisone; immune-suppressive or stimulatory agents such as methotrexate or levamasole; dentinal desensitizing agents such as potassium nitrate, strontium chloride or sodium fluoride; odor masking agents such as peppermint oil or chlorophyll; immune reagents such as immunoglobulin or antigens; local anesthetic agents such as lidocaine or benzocaine; antioxidants such as thymol, alphatocopherol and butylated hydroxy toluene; lipopolysaccharide complexing agents such as polymyxin; quaternary ammonium compounds such as benzalkonium chloride and cetyl pyridinium chloride; aromatics such as camphor, eucalyptus oil, and aldehyde derivatives such as benzaldehyde; denture adhesives such as lower alkyl vinyl ether- maleic acid or anhydride copolymers and their salts; coolants having therapeutic efficacy such as menthol; or peroxides such as urea peroxide. It is recognized that in certain forms of therapy, combinations of these agents in the same delivery system may be useful in order to obtain an optimal effect. Thus, for example, an antimicrobial and an anti-inflammatory agent may be combined in a single delivery system to provide combined effectiveness. Preferred actives are therapeutic, medicinal, pharmaceutical, and those commonly used in health care products. Preferred formulations for the present invention compositions which comprise one or more actives are dental care preparations such as dentifrices and oral rinses Dental care preparations typically comprise a soluble fluoride ion source as one of the actives. The soluble fluoride ion source is used in an amount sufficient to provide from about 10 to about 5000 ppm of the fluoride ion. Preferred fluorides are sodium fluoride, stannous fluoride, inidium fluoride, and sodium monofluorophosphate. Norris et al., U.S. Patent 2,946735, issued July 26, 1960 and Widder et al., U.S. Patent 3,678,154, issued July 18, 1972, disclose such salts as well as others. Both patents are incorporated herein by reference in their entirety. Various polymers and mixtures thereof are also useful in dental care preparations. These polymers may be synthetic anionic polymeric polycarboxylates and their complexes and/or ca-r wxyvinyl polymers. Polymers useful in the present compositions are disclosed in U.S. Patent 4,906,456 to Gaffer et al., issued March 6, 1990, incorporated herein by reference in its entirety. Pyrophosphate salts are pharmaceutical actives that may also be included in dental care preparations. Any of the alkali metal pyrophosphate salts may be used in either their hydrated or unhydrated forms. Specific salts include tetra alkali metal pyrophosphate, dialkali metal diacid pyrophosphate, trialkali metal monoacid pyrophospate and mixtures thereof wherein the alkali metals are preferably sodium or potassium. Pyrophosphate salts are described in more detail in Kirk & Othmer, Encyclopedia of Chemical Technology, Second Edition, Volume 15, Interscience Publishers (1968), incorporated herein by reference in its entirety. Anti-plaque and anti-gjngivitis pharmaceutical actives may also be included in the dental preparations. These actives include quaternary ammonium compounds or bis-biguanides such as chlorhexidine and stannous ion in the form of a combination of stannous fluoride and stannous gluconate. Oral compositions comprising stannous ion are described fully in U.S. Patent 5,004,597 to Majeti et al., issued April 2, 1991, incorporated herein by reference in its entirety. Disinfectant agents like triclosan and antiseptic agents like thymol may also be included in the dental preparations. The compositions herein , in addition to being in the form of toothpaste, nasal sprays, and mouthrinse, may be in the form of liquid or granular laundry detergents, fabric softeners, topical skin preparations, antiperspirants/deodorants, and feminine hygiene pads. All percentages and ratios used herein are by weight, and all measurements are made at 25°C, unless otherwise specified. The following examples further describe and demonstrate embodiments within the scope of the present invention. These examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention as many variations thereof are possible without departing from the spirit and scope of the present invention. Example I Toothpaste Composition A toothpaste composition according to the present invention can be prepared having the following components: Component Weight % ThMP* 1.00 Purified Water Balance Sorbitol 60.565 Sodium Fluoride (1100 ppm F") 0.243 Saccharin 0.130 Colorant 0.500 Silica 20.000 Flavor 0.500 Carboxymethyl cellulose 0.300 Xanthan Gum 0.475 Trisodium Phosphate 1.450 Monosodium Phosphate 0.590 Sodium Alkyl Sulfate Solution 4.000 (27.9% in H2O) Titanium Dioxide 0.525 *=thymyl monophosphate Add sorbitol to water and mix. Dissolve salts, ThMP, sodium fluoride, saccharin, trisodium phosphate, and monosodium phosphate. Adjust the pH to 7.0 and then add colorant. Separately combine silica, carboxymethyl cellulose, and xanthan gum and then slowly add this mixture to the composition while mixing continuously. Add sodium alkyl sulfate. Add the flavor (eg, spearmint, peppermint, wintergreen, fruit) to the composition and mix for ten more minutes. Example II Oral Mouth Rinse Composition An oral mouth rinse composition according to the present invention can be prepared having the following components: Component Weight % ThMP* 1.00 Ethanol (190 proof) 16.250 Polysorbate 80 0.120 Glycerin 10.000 Purified Water Balance Benzoic Acid 0.0045 Cetylpyridinium Chloride 0.045 Domiphen Bromide 0.005 Sodium Saccharin 0.060 Colorant 0.040 Sodium Benzoate 0.0537 *=thymyl monophosphate (prepared as described below) To ethanol, add all ingredients except ThMP and mix for 5 minutes. Add ThMP last and then adjust the pH of the composition to pH 6.0. Other compounds of the present invention can be substituted for the ThMP above, such as 2-phenoxyethanyl monophosphate, and phenoxy monophosphate. The amount of the phosphate employed in the composition can vary within the limits described herein. Preparation of Thvmyl Monophosphate In an argon-flushed, ice-cooled 250 mL, three-neck round bottom flask equipped with a mechanical stirrer, addition funnel, and temperature probe, 14 mL of triethylamine is added dropwise to 15 g of thymol dissolved in 19 mL of phosphorus oxychloride. After diluting the mixture with 50 L of diethyl ether and allowing the stirred suspension to warm to room temperature over 1 hour, the mixture is recooled in an ice bath and is carefully hydrolyzed with 50 mL of water. After about 2 hours at 0° C, the mixture is allowed to slowly warm to room temperature overnight. The aqueous layer is then extracted with diethyl ether (3 x 50 mL) and the combined ether layers are extracted with a 1 N sodium hydroxide solution (4 x 100 mL). The combined basic extracts are acidified with a 10% excess of concentrated aqueous hydrochloric acid and an oil separates out. The resulting solution and oil are extracted several times with ether (300 mL total). The combined ether extracts are dried with sodium sulfate, the mixture is filtered, and the solution is concentrated under vacuum to give a clear, viscous syrup. After further drying under vacuum with warming at 40° C, a semicrystalline solid is obtained which can be purified to a crystalline solid by trituration with w-hexane (yield: 18.5 g, 80%). Example III A heavy duty liquid detergent according to the present invention can have the following formula. Ingredients are added in the order shown according to convention. % By Ingredients Weight C14-15 alkyl polyethoxylate (2.25) sulfonic acid 10.60 C 12- 13 alkyl ethoxylate 2.40 12 C12.3 linear alkyfoenzene sulfonic acid 12.50 Sodium tartrate mono-and di-succinate (80:20 mix) 6.00 Citric acid 4.00 C12-14 fatty acid 2.00 Tetraethylene pentaamine ethyxylate (15-18) 1.50 Poly ([ 1 ,4]-B-D-glucosyl-6-(2-phenoxy-ethanylphosphate)) 0.38 (PGPEP) Protease (34g/l) 0.68 Brightener 0.15 Ethanol 1.47 Monoethanolamine 1.00 Sodium formate 0.32 1,2 propanediol 6.00 Sodium hydroxide 3.10 Silicone suds suppressor 0.0375 Sodium cumene sulfonate 6.00 Boric acid 2.00 Lipase (100 KLU/g) 0.48 Perfume 0.25 Water/miscellaneous Balance pH (10% solution) 7.8-8.3 Example IV A condensed granular detergent composition can be made according to the following composition: % By Ingredients Weight C14-15 alkyl sulfonic acid 13.00 C14-15 alkyl ether (2.25) sulfonic acid 5.50 C12-13 alkyl polyethoxylate (5.5) 1.45 Polyhydroxy C12-14 fatty acid amide 2.50 Sodium aluminosilicate 25.20 Crystalline layered silicate builder 23.30 Citric acid 10.00 Sodium carbonate To get wash pH = 9.90 Sodium polyacrylate (M.W. 2000) 2.00 PGPEP 1.24 Diethylenetriamine pentaacetic acid 0.45 Savinase® Protease Enzyme 0.70 6 Nonoylamino 6 oxo peroxycaproic acid 7.40 Sodium perborate monohydrate 2.10 Nonyl oxybenzene sulfonic acid 4.80 Brightener 0.10 Perfume 0.30 Lipase (lOOKLU/g) 0.20 *=Poly ([ 1 ,4]-B-D-glucosyl-6-(2-phenoxyethenyl phosphate) =PGPEP Example V Gel Composition A topical composition can be prepared by combining the following components utilizing conventional mixing techniques. Ingredients % Weight Deionized water qs 100 Ethanol (SD 40B alcohol) 40.0 Salicylic acid 2.0 Thymyl monophosphate 3.0 Polyacrylamide and C13-14 4.0 Isoparaffin and Lareth-7^ * Available as Sepigel from Seppic Corporation Water is added to a suitable vessel. While mixing at moderate speed (300 rpm), the polyacrylamide isoparaffin and C13- 14 isoparaffin and laureth-7 is added to the water. Next the thymyl monophosphate is added and mixed until dissolved. In a separate vessel, using a Lightnin 1 or other appropriate mixer with a 3 blade paddle prop, the salicylic acid is added to the ethanol and mixed until dissolved. The alcohol mixture is slowly added with mixing to the water phase to form a gel. The resulting gel is mixed at moderate speed until uniform.

Claims: WHAT IS CLAIMED IS : 1. A noningestible sustained release antimicrobial composition, comprising, by weight of the composition, from 0.001% to 25%, preferably from 0.01% to 15%, of one or more compounds of the formula; where R is an antimicrobial agent; R' and R" are independently selected from the group consisting of R, an adherent component, physiologically relevant metal cation, organic cation, and hydrogen; X, X 1 , and X" are independently selected from the group consisting of oxygen, nitrogen, and sulfur; and n is an integer greater than or equal to 1, preferably from 1 to 3. 2. The composition of Claim 1 where R' and R" are independently selected from the group consisting of R, C12-C18 diacyl glycerol, partially hydrolyzed vinyl acetate-ethylene copolymer, cellulose, carboxymethyl cellulose, chitin, glucosamine, silica gel, glycerol, lower alkyl vinyl ether maleic acids, sodium, potassium, calcium, zinc, magnesium, ammonium, protonated amines, partially or fully protonated amine-containing polymers, and hydrogen; and n is 1 or 2. 3. The composition of any of the preceding claims wherein the compound is selected from the group consisting of thymyl monophosphate, 2,4,4'- trichloro-2'-hydroxy-diphenyl ether monophosphate, 2-phenoxyethanyl monophosphate, and poly ([ l,4]-B-D-glucosyl-6-(2-phenoxyethanyl phos¬ phate). 4. The composition of any of the preceding claims wherein R is an antimicrobial component selected from the group consisting of 2,4,4'-trichloro-diphenyl ether-2'-yl, 2-phenoxyethanyl, chlorhexidine, and thymyl. 5. The composition of any of the preceding claims wherein the compound is thymyl monophosphate or poly ([l,4]-B-D-glucosyl-6-(2-phenoxyethenyl phosphate). 6. The composition of any of the preceding claims comprising from 0.1% to 5% of the compound. 7. The composition according to any of the preceding claims wherein the composition is in the form of a liquid or granular laundry detergent, an oral mouth rinse, or a toothpaste. 8. The composition according to any of the preceding claims wherein the composition is in the form of a topical skin preparation and the compound is 2,4,4'-trichloro-2'-hydroxy-diphenyl ether monophosphate. 9. The composition according to any of the preceding claims wherein the composition is in the form of a nasal spray and the compound is 2,4,4'- trichloro-2'-hydroxy-diphenyl ether monophosphate or thymyl monophosphate.

Inventors: HAYES JEFFREY CHARLES, NELSON DENNIS GEORGE ANTHONY, HAYES, JEFFREY, CHARLES, NELSON, DENNIS, GEORGE, ANTHONY
Applicants: PROCTER & GAMBLE, THE PROCTER & GAMBLE COMPANY
Application year: 1994
Main classification: A01N57
IPC codes: A01N57, A61K8, A61K9, A61K31, A61P31, A61Q11, A61Q19, C11D3